Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability.
Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability.
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DOI：
10.1161/hypertensionaha.108.117663
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Feener EP
中科院分区：
文献类型：
--
作者：
Phipps JA;Clermont AC;Sinha S;Chilcote TJ;Bursell SE;Feener EP
Hypertension is a leading risk factor for the development and progression of diabetic retinopathy, and contributes to a variety of other retinal diseases in the absence of diabetes. Inhibition of the renin-angiotensin system has been shown to provide beneficial effects against diabetic retinopathy, both in the absence and presence of hypertension, suggesting that angiotensin II and the AT1 receptor may contribute to retinal vascular dysfunction. We investigated the effects of the AT1 receptor antagonist candesartan on retinal vascular permeability (RVP) in normotensive rats with streptozotocin-induced diabetes and in rats with angiotensin II-induced hypertension. We show that candesartan-treatment decreased diabetes- and angiotensin II-stimulated RVP by 58% (P<0.05) and 79% (P<0.05) respectively, compared with untreated controls, suggesting that activation of the AT1 receptor contributes to blood-retinal barrier dysfunction. We found that plasma kallikrein levels are increased in the retina of rats with angiotensin II-stimulated hypertension and that intravitreal injection of either plasma kallikrein or bradykinin is sufficient to increase RVP. We show that a novel small molecule inhibitor of plasma kallikrein, 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl-benzylamide (ASP-440), delivered systemically via a subcutaneous pump, decreases angiotensin II-stimulated RVP by 70% (P<0.05) and ameliorates angiotensin II-induced hypertension, measured from the carotid artery by telemetry, but did not reduce angiotensin II-induced retinal leukostasis. These findings demonstrate that activation of the AT1 receptor increases RVP and suggest that systemic plasma kallikrein inhibition may provide a new therapeutic approach for ameliorating blood-retinal barrier dysfunction induced by hypertension.
